Mechanisms of inactivation of the tumour suppressor gene RHOA in colorectal cancer

Higinio Dopeso, Paulo Rodrigues, Josipa Bilic, Sarah Bazzocco, Fernando Cartón-García, Irati Macaya, Priscila Guimarães De Marcondes, Estefanía Anguita, Marc Masanas, Lizbeth M. Jiménez-Flores, Águeda Martínez-Barriocanal, Rocío Nieto, Miguel F. Segura, Simo Schwartz, John M. Mariadason, Diego Arango

    Research output: Contribution to journalReview articleResearchpeer-review

    13 Citations (Scopus)

    Abstract

    Background:Reduced RHOA signalling has been shown to increase the growth/metastatic potential of colorectal tumours. However, the mechanisms of inactivation of RHOA signalling in colon cancer have not been characterised.Methods:A panel of colorectal cancer cell lines and large cohorts of primary tumours were used to investigate the expression and activity of RHOA, as well as the presence of RHOA mutations/deletions and promoter methylation affecting RHOA. Changes in RHOA expression were assessed by western blotting and qPCR after modulation of microRNAs, SMAD4 and c-MYC.Results:We show here that RHOA point mutations and promoter hypermethylation do not significantly contribute to the large variability of RHOA expression observed among colorectal tumours. However, RHOA copy number loss was observed in 16% of colorectal tumours and this was associated with reduced RHOA expression. Moreover, we show that miR-200a/b/429 downregulates RHOA in colorectal cancer cells. In addition, we found that TGF-β/SMAD4 upregulates the RHOA promoter. Conversely, RHOA expression is transcriptionally downregulated by canonical Wnt signalling through the Wnt target gene c-MYC that interferes with the binding of SP1 to the RHOA promoter in colon cancer cells.Conclusions:We demonstrate a complex pattern of inactivation of the tumour suppressor gene RHOA in colon cancer cells through genetic, transcriptional and post-transcriptional mechanisms.
    Original languageEnglish
    Pages (from-to)106-116
    JournalBritish Journal of Cancer
    Volume118
    Issue number1
    DOIs
    Publication statusPublished - 1 Jan 2018

    Keywords

    • RHO signalling
    • colorectal
    • miRNA
    • transcriptional regulation

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